A descendant of missionaries and educators, Benton was greatly influenced by his indomitable mother—a professor’s widow, pioneer woman school superintendent, and Montana homesteader who instilled in him the drive to excel. As a schoolboy, he spent summers helping his mother “prove up” her homestead claim. After a year at Carleton College (Northfield, Minn.), he transferred to Yale University, where he demonstrated an ability to write, became chairman of The Yale Record, and graduated in 1921. He also made one of the most influential friendships of his life with his classmate Robert M. Hutchins.

Benton was attracted to the advertising business, and, after eight years of increasing success in New York City and Chicago, he took on as partner Chester Bowles and founded the New York agency of Benton and Bowles in 1929. The agency flourished through the Great Depression, partly because of its innovations in radio entertainment programs sponsored by advertisers. By 1935 it was the sixth largest advertising firm in the world, but Benton had grown restive in the profession and sold out to his partners for approximately $1 million.

Hutchins, who had become president of the University of Chicago, urged Benton to come to the university as a vice president, and in 1937 he agreed. His restless energy was well suited to the educational ferment Hutchins was developing there, and his advertising and radio background enabled him to develop the distinguished University of Chicago Roundtable of the air into an extremely popular national radio forum. While at the university, he played a significant role in helping one of its trustees, Paul G. Hoffman, organize the Committee for Economic Development. He was also, prior to U.S. involvement in World War II, active with Hutchins in the America First movement. There he came to know Robert E. Wood, chairman of Sears, Roebuck and Company.

Surprised to learn that the mail-order company reluctantly owned Encyclopædia Britannica, Benton suggested that Sears give the encyclopaedia to the university, and Wood shortly thereafter agreed. But the trustees were hesitant to take on responsibility for operating capital and general management, and Benton offered to put up his own money. The university accepted the gift, committing management and common stock to Benton and retaining preferred stock and a royalty contract. Later Benton acquired all the stock, and the royalty arrangements were modified; by the year after his death, the accumulated royalties to the university amounted to $47.8 million.

In 1945 Benton resigned from the university to become U.S. assistant secretary of state. He converted for peacetime use the U.S. Information Service, the cultural exchange programs, and the Voice of America, and he organized U.S. participation in the establishment of UNESCO, in which he later (1963–69) served as U.S. representative. He also lobbied the Fulbright Scholarship Act and the Foreign Service Act of 1946 through Congress.

Appointed to a vacant U.S. Senate seat from Connecticut in 1949, Benton was elected as a Democrat in 1950 to the remaining two years of that term. In the Senate he was among the first to decry the tactics for which Sen. Joseph R. McCarthy of Wisconsin was eventually censured. He was defeated for a full term in the Republican electoral landslide of 1952.

Thereafter, for the first time since 1945, he devoted sustained attention to Encyclopædia Britannica, Inc., which he led on an unprecedented course of acquisition and expansion. He acquired an educational filmmaker, ERPI, from Western Electric and renamed it Encyclopædia Britannica Films (1943; later given to his four children); he published the 54-volume Great Books of the Western World (1952) and Enciclopedia Barsa (Spanish, 1957; Portuguese, 1964); and he set in motion joint ventures leading to the publication of major foreign encyclopaedias (Encyclopædia Universalis, French, 1968–75; Britannica International Encyclopædia, Japanese, 1972–75). He acquired Compton’s Pictured Encyclopedia (1961), G. & C. Merriam Company (1964; Webster’s dictionaries), and Frederick A. Praeger, Inc. (1964–76). Shortly thereafter he authorized a massive effort to create the 15th edition of the Britannica, the costs of which were ultimately $32 million. He died a year before publication. In accordance with his wishes, ownership of the Britannica went to the William Benton Foundation, a support foundation for the University of Chicago; the foundation held the Britannica until 1996.

His own writings include two books: This Is the Challenge (1958) and The Voice of Latin America (1961). In 1968 Benton was honoured by the University of Chicago with the first William Benton Distinguished Service Medal.

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